Search

Shazia Bano,1–3 Samina Nazir,2 Alia Nazir,1 Saeeda Munir,3 Tariq Mahmood,2 Muhammad Afzal,1 Farzana Latif Ansari,4 Kehkashan Mazhar3 1Department of Physics, The Islamia University of Bahawalpur, Bahawalpur, 2Nanosciences and Technology Department, National Centre for Physics, 3Institute of Biomedical and Genetic Engineering (IBGE), 4Pakistan Council for Science and Technology, Islamabad, Pakistan Abstract: Superparamagnetic iron oxide nanoparticles (SPIONs) have the potential to be used as multimodal imaging and cancer therapy agents due to their excellent magnetism and ability to generate reactive oxygen species when exposed to light. We report the synthesis of highly biocompatible SPIONs through a facile green approach using fruit peel extracts as the biogenic reductant. This green synthesis protocol involves the stabilization of SPIONs through coordination of different phytochemicals. The SPIONs were functionalized with polyethylene glycol (PEG)-6000 and succinic acid and were extensively characterized by X-ray diffraction analysis, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy, Rutherford backscattering spectrometry, diffused reflectance spectroscopy, fluorescence emission, Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, and magnetization analysis. The developed SPIONs were found to be stable, almost spherical with a size range of 17–25 nm. They exhibited excellent water dispersibility, colloidal stability, and relatively high R2 relaxivity (225 mM-1 s-1). Cell viability assay data revealed that PEGylation or carboxylation appears to significantly shield the surface of the particles but does not lead to improved cytocompatibility. A highly significant increase of reactive oxygen species in light-exposed samples was found to play an important role in the photokilling of human cervical epithelial malignant carcinoma (HeLa) cells. The bio-SPIONs developed are highly favorable for various biomedical applications without risking interference from potentially toxic reagents. Keywords: green approach, biocompatible, multifunctional, bio synthesis, surface modification, microwave incubation, MRI contrast agent, photosensitive SPIONs

The present study describes the investigation of the binding modes of potential anti-cancerous nitrophenyl derivatives of 2-(x-nitrophenyl)-5-nitrobenzimidazole with calf thymus DNA. The -2-(x-nitrophenyl)-5-nitrobenzimidazoles under investigation differ only in position x of nitro group in nitrophenyl substituent relative to benzimidazole moiety leading to 1-NPNB (x = 2), 2-NPNB (x = 3) and 3-NPNB (x = 4). The DFT calculations predicted that derivatives were electrochemically reducible which was then confirmed by cyclic voltammetry. In cyclic voltammetry, the second reversible peak was dependent on first irreversible reduction. This revealed that electrochemical irreversible process was governed by some other process which was then followed by reversible second electron transfer. Thus, ECE (electron transfer leading to coupled chemical reaction followed by another electron transfer process) mechanism was attributed for electrochemical reduction. Experimental results based on UV-Vis spectroscopy vaguely showed intercalation of 1-NPNB, 2-NPNB and 3-NPNB into DNA which was assisted by cyclic voltammetry. However, thermal melting and florescence spectroscopy unambiguously established intercalation for all three compounds. Molecular docking analysis ascertained in pocket stacking of 5-nitrobenzimidazole moiety in 1-NPNB and 2-NPNB while nitro phenyl substitution in 3-NPNB stacks between DNA base pair during intercalation which was in agreement with DFT computed molecular geometry. Therefore, the relative positions of nitro group and 5-nitrobenzimidazole moieties in 2-(x-nitrophenyl)- 5-nitrobenzimidazole influenced the DNA binding pattern of compounds during intercalation. The cytotoxicity of these compounds was comparable to standard drug doxorubicin against both cancerous (MCF-7) and normal (MCF-10A) breast cells which depicts their anti-cancerous potential., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier B.V.)

Thymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC 50  = 1.09 ± 0.004 μM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Superparamagnetic iron oxide nanoparticles (SPIONs) have the potential to be used as multimodal imaging and cancer therapy agents due to their excellent magnetism and ability to generate reactive oxygen species when exposed to light. We report the synthesis of highly biocompatible SPIONs through a facile green approach using fruit peel extracts as the biogenic reductant. This green synthesis protocol involves the stabilization of SPIONs through coordination of different phytochemicals. The SPIONs were functionalized with polyethylene glycol (PEG)-6000 and succinic acid and were extensively characterized by X-ray diffraction analysis, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy, Rutherford backscattering spectrometry, diffused reflectance spectroscopy, fluorescence emission, Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, and magnetization analysis. The developed SPIONs were found to be stable, almost spherical with a size range of 17-25 nm. They exhibited excellent water dispersibility, colloidal stability, and relatively high R 2 relaxivity (225 mM(-1) s(-1)). Cell viability assay data revealed that PEGylation or carboxylation appears to significantly shield the surface of the particles but does not lead to improved cytocompatibility. A highly significant increase of reactive oxygen species in light-exposed samples was found to play an important role in the photokilling of human cervical epithelial malignant carcinoma (HeLa) cells. The bio-SPIONs developed are highly favorable for various biomedical applications without risking interference from potentially toxic reagents.

In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 μg/ml and 1.5 μg/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

1,4-Disubstituted-1,2,3-triazoles were synthesized by Cu(I) catalyzed click reaction, where the azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1-ethynyl-1-cyclohexanol served as the terminal alkyne. These synthesized triazoles were subjected to enzymatic assay which showed promising activity against α-glucosidase; 1-(2-cyano-4-nitrophenyl)-4-(1-hydroxycyclohexyl)-1H-1,2,3-triazole 3m being the most active members of the library. Molecular docking studies of these triazoles with the homology-modeled α-glucosidase protein were also performed to delineate ligand-protein interactions at molecular level which suggested that Phe157, Arg312 and His279 are the major interacting residues in the biding site of the protein and may have a significant role in the inhibition of enzyme's function., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A striking dual inhibition of enzymes α-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimer's disease. These findings will be instrumental for rational design of drug candidates for both of these conditions., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Context: In the course of searching potential antitumor agents from a library of chalcones synthesized under microwave irradiations, the brine shrimp lethality (BSL) assay and a 3D structure-activity relationship (3DQSAR) studies were followed by the antitumor evaluation of most potent analogues., Objective: The objective of the current study was to effectively use the BSL assay for the identification of potential cytotoxic analogues from a set of compounds., Methods: We applied the comparative molecular field analysis (CoMFA) and devised 3DQSAR on 33 synthesized chalcones leading to prediction of five related compounds with improved activity. The scope of BSL assay for the prediction of antitumor potency was tested through the in vitro antitumor studies against six human tumor cell-lines, docking studies and the tubulin-polymerization assay., Results: The newly designed compounds 34-38 displayed very promising cytotoxic potency. From our results, the BSL toxicity, antitumor efficacy and docking outcomes could be easily co-related., Conclusion: The study draws a very good relationship between a simple, inexpensive, and bench-top BSL assay and the antitumor potential of the cytotoxic compounds. Devising the CoMFA analysis helped in designing chalcones with improved cytotoxic potential as displayed through their BSL and cytotoxic activity against human tumor cell lines. The studies are noteworthy as such comprehensive studies were never performed before on the BSL assay. The present studies widen the scope of the BSL model that may prove quite helpful as a preliminary screen in the antitumor drug designing and synthesis expeditions.

Medicinal chemists are facing an increasing challenge to deliver safer and more effective medicines. An appropriate balance between drug-like properties such as solubility, permeability, metabolic stability, efficacy and toxicity is one of the most challenging problems during lead optimization of a potential drug candidate. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. The weak inhibitory activity and non-drug-like properties of monastrol, the first small mitotic kinesin Eg5 inhibitor, has hampered its further development. In this investigation, a bioisosteric approach was applied that resulted in the replacement of C-5 carbonyl of monastrol with thio-carbonyl. Further lead optimization of drug-like properties was evaluated through in silico predictions by using ADMET predictor software. This minor structural modification resulted in upgraded human effective jejunal permeability (Peff) and improved permeability in Madin-Darby canine kidney (MDCK) cells. Furthermore, C-5 thiocarbonyl analogue of monastrol (named as Special-2) was found safe to administer orally with no phospholipidosis toxicity, no raised levels of serum glutamate oxaloacetate transaminase (SGOT) and no potential towards cardiotoxicity. Molecular docking study was also carried out to understand the binding modes of these compounds. The docking study showed high binding affinity of the designed compounds against KSP. Hence a combination of in silico ADMET studies and molecular docking can help to improve prediction success and these compounds might be act as potential candidate for KSP inhibition., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in-house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Fourteen new N-acetylated and non-acetylated pyrazoline derivatives were synthesized by reacting chalcones with hydrazine in the presence of absolute ethanol however reaction was carried out in the presence of glacial acetic acid to afford N-acetylated pyrazolines. The chemical structures of the synthesized pyrazolines were confirmed by FTIR, (1)HNMR, (13)CNMR and mass spectroscopic data. The pyrazolines (1-14) were screened for antibacterial activity against ten bacterial strains using seven Gram-positive and three Gram-negative bacteria and antifungal activity against Aspergillus flavus, Aspergillus niger and Aspergillus pterus. Pyrazolines (1-14) found to exhibit good to excellent antimicrobial activities compared to the levofloxacin and fluconazole used as standard drugs.

In continuation to our efforts in finding potential therapeutic agents, a variety of biologically significant semicarbazones were synthesized by the reaction of different carbonyl compounds with phenyl semicarbazides through microwave irradiation. Initially, 18 semicarbazones were studied for their antimicrobial, antitumor, and antioxidant potential. None of the tested compounds showed any antibacterial activity; however, some compounds showed significant antifungal activity. Interestingly, all compounds showed antitumor activity when tested against tumors grown on potato discs. These compounds were also tested for their effect on OH radical-induced oxidative DNA damage. All the compounds showed DNA protection to varying extent. Based on the promising results of antitumor and antioxidant activities, another set of 24 semicarbazones was synthesized, and all of these semicarbazones were evaluated for their antioxidant potential. The results showed that the semicarbazones derived from 2-nitrobenzaldehyde and acetophenone were the most active 2,2-diphenyl-1-picrylhydrazyl 9 (DPPH) free radical scavengers. The overall results have led to the identification of some interesting compounds which seem to have great potential to be developed into effective anticancer drugs., (© 2012 John Wiley & Sons A/S.)

The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.

The synthesis of some novel alkyl/aryl substituted tertiary alcohols was accomplished in two steps. The synthetic route involves preparation of Grignard reagents by treating alkyl/aryl bromides with magnesium turnings in dry ether. Then substituted chalcones were reacted with the Grignard reagents to afford alkyl/aryl substituted tertiary alcohols 1-10. The structures of the synthesized compounds were assigned on the basis of FT-IR, 1H-NMR, 13C-NMR and mass spectroscopic data. The in vivo anti-inflammatory activity of the synthesized compounds was evaluated using the carrageenan-induced hind paw edema method and was compared with that of ibuprofen. Some of the newly synthesized compounds showed promising anti-inflammatory activity. The tertiary alcohols 1-10 were also screened for antibacterial activity against ten bacterial strains using seven Gram-positive and three Gram-negative bacteria and for antifungal activity against Aspergillus Flavus, Aspergillus Niger and Aspergillus pterus. Tertiary alcohols 1-10 were found to exhibit good to excellent antimicrobial activities compared to levofloxacin and fluconazole used as standard drugs.

Background: Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by beta-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of beta-amyloid plaques., Rationale: We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases., Conclusion: Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-pi, pi-pi interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.

In continuation of our previous study on the urease inhibition by a number of chalcones, 2,3-dihydro-1,5-benzothiazepines and 2,3,4,5-tetrahydro-1,5-benzothiazepines, FlexX docking has been exploited to get a deeper insight into the mechanism of their inhibitory action. A comparison of the IC(50) values of the active compounds reveals that, of the three classes of compounds studied, 2,3-dihydro-1,5-benzothiazepines were the most potent urease inhibitors. An in silico examination of these compounds showed that the activity is related to the interaction of ligand with the nickel metallocentre, its interaction with two amino acid residues, Asp224 and Cys322, in addition to the orientation of rings A and B in the catalytic core of the enzyme. The most active compound 2,3-dihydro-1,5-benzothiazepine (4) anchor tightly through a network of interactions with Ni701 and Ni702. This includes a number of hydrogen bonds and hydrophobic contacts with the amino acid residues in its vicinity. For their reduced analogs, the difference in the activity of different diastereomers has been observed to be configuration-dependent. This may be ascribed mainly to the difference in the orientation of ring B of the two stereoisomers and the extent of their interaction with Asp224 and Cys322 present in the catalytic core of the enzyme.

Solid-phase synthesis of a parallel library of 3'-hydroxy-2,3-dihydrobenzothiazepines has been carried out through [4+3] annulation of alpha,beta-unsaturated ketones with aminothiophenol, using Wang resin as solid support. The synthesized compounds were evaluated for their potential as antibacterial, tumor inhibitors as well as acetyl- and butyrylcholinesterase inhibitors. None of the compounds showed any significant antibacterial activity. However, quite a few compounds showed significant potential as crown gall tumor inhibitors. These results reflect a strong exploratory potential in search of new benzothiazepines as source of anticancer agents. The results of the inhibition of cholinesterase revealed that benzothiazepines have a greater potential as butyrylcholinesterase inhibitors as compared to acetylcholinesterase. Moreover, the substitution of hydroxy group at C-3 in ring A led to increased activity when compared to unsubstituted- and 2'-OH substituted benzothiazepines.

The interaction of anticancer chalcone [AMC, 1-(4'-aminophenyl)-3-(4-N,N-dimethylphenyl)-2-propen-1-one] with DNA has been explored using electrochemical, spectroscopic and viscometric techniques. A shift in peak potential and decrease in peak current were observed in cyclic voltammetry and hypochromism accompanied with bathochromic shift were noticed in UV-Vis absorption spectroscopy. These findings were taken as evidence for AMC -DNA intercalation. A binding constant (K) with a value of 6.15 x 10(5) M(-1) was obtained from CV data, which was also confirmed by UV-Vis absorption titration. Moreover, the diffusion coefficient of the drug with and without DNA (D(b) and D(u)), heterogeneous electron transfer rate constant (k(o)) and electron affinity (A) were also calculated from electrochemical data.

Benzothiazepines 1-3 inhibited acetylcholinesterase (AChE; EC 3.1.1.7) enzyme in a concentration-dependent fashion with IC(50) values of 1.0 +/- 0.002, 1.2 +/- 0.005 and 1.3 +/- 0.001 microM, respectively. By using linear-regression equations, Lineweaver-Burk, Dixon plots and their secondary replots were constructed which indicated that compounds 1-3 are non-competitive inhibitors of AChE with K(i) values of 0.8 +/- 0.04, 1.1 +/- 0.002, and 1.5 +/- 0.001 microM, respectively. Molecular docking studies revealed that all the compounds are completely buried inside the aromatic gorge of AChE, extending deep into the gorge of AChE. A comparison of the docking results of compounds 1-3 displayed that these compounds generally adopt the same binding mode in the active site of AChE. The superposition of the docked structures demonstrated that the non-flexible benzothiazepine always penetrate into the aromatic gorge through the six-membered ring A, which allowed the ligands to interact simultaneously with more than one subsites of the active center of AChE. The higher AChE inhibitory potential of compounds 1-3 was found to be the cumulative effect of hydrophobic contacts and pi-pi interactions between the ligands and AChE. The relatively high affinity of benzothiazepine 1 with AChE was found to be due to additional hydrogen bond in benzothiazepine 1-AChE complex. The results indicated that substitution of halogen and methyl groups by hydrogen at aromatic ring of the benzothiazepine decreased the affinity of these molecules towards enzyme that may be due to the polar non-polar repulsions of these moieties with the amino acid residues in the active site of AChE. The observed binding modes of benzothiazepines 1-3 in the active site of AChE explain the affinities of benzothiazepines and provide a rational basis for the structure-based drug design of benzothiazepines with improved pharmacological properties.

A 175-member chalcone library was designed and synthesized from seven differently substituted acetophenones (A(1)-A(7)) and 25 differently substituted aryl or heteroaryl aldehydes (B(1)-B(25)). Potential lead compounds were identified by deconvolution of a two-dimensional library matrix via positional scanning, and the members of the most-active sub-libraries were synthesized and screened against crown-gall tumors with the aid of the potato-disc assay. The resulting hits gave rise to significant antitumor activities, with no antibacterial effect on the tumor-producing bacterium Agrobacterium tumefaciens. Two identified lead structures, (2E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one (A(1)B(9)) and the hydroxy analogue (2E)-3-(2-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (A(2)B(9)), are promising candidates to be developed into highly effective anticancer chemotherapeutics.

A 120-membered chalcone library has been designed and prepared from six differently substituted acetophenones (A1-A6) and 20 benzaldehydes (B1-B20). The library was subjected to biological studies targeted against six bacterial strains. For the identification of the most-active member(s) of the library, the so-called indexed or positional-scanning method was applied. Six out of 26 sub-libraries, i.e., AL1-AL6, were synthesized by keeping the acetophenone moiety A fixed and using equimolar quantities of the 20 different benzaldehydes. The remaining 20 sub-libraries BL1-BL20 were prepared by keeping the benzaldehyde B component fixed and varying the six acetophenones (Table 1). The bactericidal activities of the resulting sub-libraries were tested and used as indices to the rows or columns of a two-dimensional matrix. Finally, parallel synthesis of 24 specific members with the highest-expected antibacterial activities, present in two sub-libraries, was carried out. These chalcones were screened again, and the results were exploited for establishing the structure-activity relationship (SAR) and the identification of the lead compound, which turned out to be 1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (A2B2) in terms of activity towards Staphylococcus aureus and Bacillus subtilis (Tables 5-7).

A series of 2,4-diaryl-2,3,4,5-tetrahydro- (36-40) and 2,4-diaryl-2,3-dihydro-1,5-benzothiazepines (25-35) have been synthesized from the corresponding chalcones 1-24. Both the benzothiazepines and chalcones were evaluated as DPPH free-radical scavengers and as inhibitors of cholinesterases, urease, and alpha-glucosidase. Compounds 2, 5, 6, 7, 10, 13, 18, 21, 36a, 37a, 37b, and 39a showed significant cholinesterase inhibiting activities. Among the 15 dihydro-1,5-benzothiazepines, 26, 32, and 35 exhibited significant radical-scavenging activities; and six tetrahydro-1,5-benzothiazepines (35, 36a, 36b, 37a, 37b, and 39a) were found to be inhibitors of AChE and BChE. Compounds 22, 25, 26, 33, 35, 36a, 37b, and 39a inhibited urease, and 25 and 27-31 were found to be potent inhibitors of alpha-glucosidase.

The electron ionization induced fragmentations of ten biologically significant 2,3-dihydro-1,5-benzothiazepines and the corresponding 2,3,4,5-tetrahydro-1,5-benzothiazepines have been studied by low- and high-resolution mass spectrometry. The fragmentations follow a general pattern, the details of which are discussed with respect to the nature and position of the substituent in the aromatic ring. The dihydro- and tetrahydro-1,5-benzothiazepines both undergo fragmentation through four routes (A-D). However, the most significant fragmentation takes place through route A, leading to the elimination of ring A or ring B of the molecule. The difference between the fragmentation patterns of dihydro- and tetrahydro-1,5-benzothiazepines appears mainly in route E where a phenylallylhydroxybenzene cation appears in all tetrahydro-1,5-benzothiazepines but is not observed in the corresponding dihydro derivatives., (Copyright 2005 John Wiley & Sons, Ltd.)

In the structures of 2-(4-chlorophenyl)-4-(2-hydroxyphenyl)-2,3-dihydro-1,5-benzothiazepine, C(21)H(16)ClNOS, 4-(2-hydroxyphenyl)-2-(4-tolyl)-2,3-dihydro-1,5-benzothiazepine, C(22)H(19)NOS, and 4-(2-hydroxyphenyl)-2-(3-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine, C(22)H(19)NO(2)S, the central seven-membered heterocyclic rings adopt twist-boat conformations in which the N atoms are involved in strong intramolecular hydrogen bonds with the hydroxyl H atoms, resulting in six-membered rings.